The injection of a material (an "injectate") into the body, and particularly into the face, to effect an aesthetic result dates to the close of the nineteenth century. For example, the injection of paraffin to correct facial contour defects enjoyed a brief period of acceptance in the years prior to World War I. However, complications and the unsatisfactory nature of the long-term results caused the practice to be abandoned. The availability of injectable silicone gave rise to a virtual repetition of these events beginning in the early 1960's. Specially manufactured "medical grade" silicone solutions, e.g., Dow Corning MDX 4.4011, have been used on an experimental basis in a number of approved test centers in the United States. Complications, such as local and systemic reactions to the silicone, migration of the injectate, and local tissue break down, have limited the use of Silicone injections. Although the original proponents of silicone injections have continued their experimental programs with a limited number of subjects, it appears very unlikely that the technique will be adopted by the larger community of surgeons and physicians. Reviewed in Matton, G., et al., 1985, Aesthetic Plastic Surgery 9:133-40; Spira, M. & Rosen, T., 1993, Clin. Plastic Surgery 20:181-9.
The poor results obtained by the injection of non-biological materials have prompted attempts to use foreign proteins, particularly bovine collagen, as an injectate. Although unprocessed bovine collagen is too immunogenic for injection into humans, the removal by enzymatic degradation of C- and N-terminal peptides of bovine collagen yields a material ("atelocollagen") that can be used in limited quantities if patients are pre-screened to exclude those patients who are immunoreactive. Methods of preparing and using such products are described in U.S. Pat. No. 3,949,073, U.S. Pat. No. 4,424,208 and U.S. Pat. No. 4,488,911. The product has been sold as ZYDERM.RTM. brand of atelocollagen in solution at concentrations of 35 mg/ml and 65 mg/ml. Although in widespread world wide use, as of 1987 there more than 200,000 subjects in the United States, the use of ZYDERM is associated by the development of anti-bovine antibodies in about 90% of subjects and with overt immunologic complications in about 1-3% of subjects. DeLustro, F., et al., 1987, Plastic and Reconstructive Surgery 79:581.
Atelocollagen in solution proved to be less than completely satisfactory because the material is, within a period of weeks to months, absorbed by the subject from the site of injection without replacement by host material. Although protocols consisting of repeated injections have been contemplated, such programs are, in practice, limited by the development of immune reactions to the bovine atelocollagen, expense, and by patient resistance. To overcome these limitations, bovine atelocollagen was further processed with glutaraldehyde cross-linking, followed by filtration and shearing by passage through fine mesh. The production and use of this material is described in U.S. Pat. No. 4,582,640 and U.S. Pat. No. 4,642,117. A product produced accordingly is sold as ZYPLAST.RTM. brand of cross-linked bovine atelocollagen. The advantage that cross-linking is intended to provide, an increased resistance to host degradation, is off-set by an increase in viscosity. The increased viscosity and, particularly, the irregular viscosity ("lumpiness") renders the material more difficult to use and even makes it unusable for certain purposes. See, e.g., U.S. Pat. No. 5,366,498.
Moreover, some investigators report that there is no or only marginally increased persistence of ZYPLAST compared to ZYDERM and that the duration of an injections' effects is at most about 4 to 6 months. Matti, B. A. & Nicolle, F. V., 1990, Aesthetic Plastic Surgery 14:227-34; Ozgentas, H. E. et al., 1994, Ann Plastic Surgery 33:171. In the experience of most practitioners there is noticeable absorption after about 4 to 6 weeks.
The limitations imposed by the immunogenicity of bovine collagen products in humans have caused others to consider the preparation of human collagen from placenta, see, e.g., U.S. Pat. No. 5,002,071 and from surgical specimens, see, e.g., U.S. Pat. No. 4,969,912 and U.S. Pat. No. 5,332,802. Further processing of human collagen by cross-linking and other chemical modifications is required because human collagen is subject to the same degradative process as bovine collagen.
Human collagen for injection that is derived entirely from a sample of the subjects own tissue is available and sold under the brand name AUTOLOGEN.TM.. There is no evidence that human collagen injections result in more persistent effects than bovine collagen injections. Further, the use of autologous processed collagen is limited to subjects who have undergone a face-lift procedure, because the starting material for its production is the skin removed during this operation. Clearly then, although autologous processed collagen overcomes the immunogenicity of bovine collagen, it, like bovine collagen, does not provide long-term therapeutic benefits and is limited to patients who have undergone surgery.
Others have injected a mixture of gelatin powder, .epsilon.-aminocaproic acid and the subject's plasma ("FIBREL.TM.") as an alternative to atelocollagen for the purpose of augmenting the subadjacent dermis. Multicenter trial, 1987, J. Am. Acad. Dermatol. 16:1155-62.
FIBREL.TM.'s action appears in part to depend upon the induction of a sclerogenic, inflammatory response to augment the soft tissue. Gold, M. H., 1994, J. Dermatologic Surg. Oncol. 20:586-90. Although the reports of FIBREL.TM. treatments state that they benefit a fraction of patients, see, e.g., Millikan, L., et al., 1991, J. Dermatologic Surg. Oncol. 17:223-29, the results can suffer from lumpiness and a lack of persistence. The use of FIBREL.TM. has also been limited by the discomfort associated with the injections, and because physicians have found its preparation tedious.
In summary, none of the available non-living injectable materials is wholly satisfactory for the purpose of augmenting the subadjacent dermis and soft tissue.
The inability to obtain long-lasting results with atelocollagen injectates and the problems of using FIBREL.TM. have prompted some to attempt to obtain and inject (graft) living adipose tissue to augment the subadjacent dermis and soft tissue. Good results in the correction of major defects can be obtained when adipose tissue is surgically removed and reimplanted. See, e.g., McKinney, P. & Pandya, S., 1994 Aesthetic Plastic Surgery 18:383-5; Davies, R. E. et al., 1995 Arch of Otolaryngology--Head & Neck Surgery 121:95-100. However, for repairs that require placement of the graft by injection, the results are decidedly less favorable. Ersek, R. A., 1991, Plastic & Reconstructive Surgery 87:219-27. Thus, even though some beneficial results have been reported, see, e.g., Hambley, R. M. & Carruthers, J. A., 1992, J. Derm. Surgery & Oncol. 18:963-8, the proponents of the method concede that for most practitioners the technique has yielded unsatisfactory results. Lewis, C. M., 1993, Aesthetic Plastic Surgery 17:109-12. Among the problems commonly encountered by physicians and subjects are the unpredictability and lumpiness of the results, which renders the procedure unsuited for treating fine wrinkles, and a period of extreme post-injection swelling, which lasts between 4-6 weeks.